Scientists at St. Jude Children's Research
Hospital have discovered that the shape of a protein on the surface of
pneumonia bacteria helps these germs invade the human bloodstream. This
finding, published Dec. 16 online by the EMBO Journal, could help
scientists develop a vaccine that is significantly more effective at
protecting children against the disease. The St. Jude researchers
determined the shape of a large, paddle-like molecule that
Streptococcus pneumoniae bacteria use to latch onto cells lining the
throat and lungs. The protein, called CbpA, binds to a molecule on the
cell called pIgR, which takes antibodies from the bloodstream on one
side of the cell and transports them to the other side. There it
releases the antibody at the lining of the throat and lungs. If a
pneumococcus bacterium is hovering on the lining of the respiratory
tract, this germ binds to pIgR and pushes this antibody shuttle back
through the cell to the bloodstream. Once at the other side of the
cell, the pneumococcus breaks free of pIgR and enters the blood, where
it can multiply and infect the body.

S. pneumoniae is the only bacterium known to use CbpA to invade human
cells by binding to pIgR, according to Richard W. Kriwacki, Ph.D.,
associate member of St. Jude Structural Biology. Kriwacki is senior
author of the EMBO Journal report.
“The fact that we now know the structure of this important protein
means we can begin to develop a vaccine that is more effective in
children than those that are currently available,?Kriwacki said.
Elaine Tuomanen, M.D., chair of Infectious Diseases and director of the
Children’s Infection Defense Center at St. Jude, is co-author of the
EMBO Journal paper. “Using CbpA as the key part of a new vaccine
against S. pneumoniae would solve a problem that now hinders our
ability to protect children from this infection,?Tuomanen said.
Current pneumonia vaccines designed to protect adults against more than
two dozen strains of S. pneumoniae do not work in
young children. Adult
vaccines are composed of pieces of carbohydrates naturally appearing on
the surface of these bacteria. When used in a vaccine, these pieces of
carbohydrate stimulate the immune system to make antibodies against the
real carbohydrate targets on the bacteria. The problem with such
vaccines is that the immune systems of very young children (younger
than two years) do not naturally respond to carbohydrates. Pneumococcus
vaccines for children must instead be modified by binding those
carbohydrates to special proteins that stimulate the immune systems of
young children. “However such vaccines are so complex that they can
carry carbohydrate targets for only a few specific strains of pneumonia
bacteria,?Tuomanen said. “So children are always under-protected,
since there are so many different strains of these bacteria.?Knowing
the shape of CbpA will guide researchers in their efforts to use part
or all of this protein as the basis of a vaccine against S. pneumoniae.
“CbpA is a very large protein,?Tuomanen said. “Now that we know what
it looks like and how it’s put together, we can pull it apart to see if
smaller pieces of it can be used to make a vaccine that triggers
production of antibodies against the CbpA. Since all the S. pneumoniae
strains need CbpA to invade the bloodstream, we can widen the
protection of a vaccine to all 90 types of pneumococcus by just adding
CbpA, or a piece of CbpA.?The discovery of the structure of CbpA was a
two-step process that included studies of how this protein works,
followed by determination of its actual structure using powerful
laboratory tools. Previous work by another team suggested that CbpA
binds to pIgR. However, that finding was made in “test-tube?experiments without using actual bacteria. So the St. Jude team
developed pneumococcus bacteria that had mutated CbpA in order to prove
that live bacteria with mutated CbpA could not bind to pIgR on cells.
“Our work confirmed that the pneumococcus uses CbpA to bind
to human
cells,?said Beth Mann, a research laboratory specialist in Tuomanen’s
lab who developed the bacteria carrying mutated CbpA. Mann, co-author
of the paper, also showed that the long, paddle-shaped extensions of
the protein must be folded in a specific way in order for CbpA to work.
The discovery of the actual shape of CbpA was made using nuclear
magnetic resonance (NMR) spectroscopy and circular dishroism (CD). NMR
combines radio wave emissions and a powerful magnetic field to
determine the structure of proteins suspended in solutions, while CD
measures differences in the absorption of different types of polarized
light by molecules to determine their shape. It also can show how that
shape can change when the protein interacts with another molecule.
“This work required that we develop new NMR methods in order to
determine the shape of this protein, which undergoes changes as it
interacts with pIgR,?said Rensheng Luo, Ph.D., a post-doctoral fellow
in St. Jude Structural Biology and Infectious Diseases and first author
of the paper.'"/>

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